Microorganisms such as bacteria may communicate via a phenomenon termed quorum sensing (QS), in which they secrete chemical signal molecules termed autoinducers into their surrounding environment. Concentration of these signal molecules may increase locally as a result of increase in cell density, such that upon reaching a threshold level when the cell population is ‘quorate’, the population activates a coordinated cellular response, such as production of virulence factors and growth as a biofilm community.
Taking Pseudomonas aeruginosa (or simply P. aeruginosa) as an example, it is a ubiquitous Gram-negative bacterium which is responsible for many opportunistic and nosocomial infections. For example, it is an opportunistic human pathogen that can cause chronic infections in immunocompromised individuals, including cystic fibrosis and intensive-care-unit patients. Notably, chronic infection by P. aeruginosa is the leading cause of death of cystic fibrosis patients.
P. aeruginosa has three main quorum sensing systems. The first two quorum sensing systems, LasR-LasI and RhlR-RhlI, are based on the LuxR-LuxI homologues of Vibrio fischeri, which makes use of acyl homoserine lactone (AHLs) as signal molecules. The AHL synthases are LasI and RhlI, which produce N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-butanoylhomoserine lactone (BHL), respectively. The receptor for OdDHL is the LasR protein, while the receptor for BHL is the RhlR protein. Together, the las and rhl quorum sensing systems regulate a host of virulence factors such as exoproteases (an example being elastase), siderophores, and toxins.
The third signaling system utilizes another kind of signal molecule, 2-heptyl-3-hydroxy-4-quinolone, that has been termed the Pseudomonas quinolone signal (PQS) and is able to affect the expression of Las and Rhl-controlled genes. LasR is an attractive target for quorum sensing inhibition as LasR controls the other quorum sensing circuits (namely Rhl and PQS) within the P. aeruginosa hierarchy. The las and rhl systems are at the top and bottom of the hierarchy respectively, while the PQS system intervenes between them.
During infection, the Gram-negative bacterium may reside within multicellular bacterial communities termed biofilms, which are characterized by their extreme tolerance towards conventional antimicrobial agents. P. aeruginosa biofilms also have an almost infinite capacity to evade and counter host innate immune responses through secretion of virulence factors, such as a rhamnolipid-based shield.
As quorum sensing controls the expression of multiple virulence factors in different bacteria, blocking or inhibition of quorum sensing would be vital in attenuating the virulence of pathogenic bacteria, and for downplaying biofilm defenses against host attacks, leading to more efficient clearing of the bacterial infection. Further, as quorum sensing inhibitors (for short, QSIs) function as an antimicrobial agent by interrupting bacterial communication, which is a non-essential process, strong selective pressure for the evolution of resistance mechanisms is not exerted, as compared to conventional growth-inhibitory compounds which inhibit growth of the microorganisms.
In view of the above, there exists a need for an improved method of inhibiting quorum sensing in microorganisms such as Pseudomonas aeruginosa that addresses or alleviates one or more of the above mentioned problems.